EP2085081A1 - 3-(2-dimethyl amino methyl-cyclohexyl) phenol for treating polyneuropathic pain - Google Patents

3-(2-dimethyl amino methyl-cyclohexyl) phenol for treating polyneuropathic pain Download PDF

Info

Publication number
EP2085081A1
EP2085081A1 EP08002013A EP08002013A EP2085081A1 EP 2085081 A1 EP2085081 A1 EP 2085081A1 EP 08002013 A EP08002013 A EP 08002013A EP 08002013 A EP08002013 A EP 08002013A EP 2085081 A1 EP2085081 A1 EP 2085081A1
Authority
EP
European Patent Office
Prior art keywords
pain
polyneuropathy
dosage form
use according
phenol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08002013A
Other languages
German (de)
French (fr)
Inventor
Thomas Dr. Christoph
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Priority to EP08002013A priority Critical patent/EP2085081A1/en
Priority to EP09708857A priority patent/EP2259783A2/en
Priority to PCT/EP2009/000655 priority patent/WO2009098008A2/en
Priority to US12/364,108 priority patent/US20090197960A1/en
Priority to CA2712637A priority patent/CA2712637A1/en
Publication of EP2085081A1 publication Critical patent/EP2085081A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the treatment of polyneuropathic pain, in particular in diabetic polyneuropathy or chemically induced polyneuropathy, by administration of 3- (2-dimethylaminomethylcyclohexyl) phenol, preferably of (1R, 2R) -3- (2-dimethylaminomethylcyclohexyl ) -phenol, or one of its pharmaceutically acceptable salts.
  • Neuropathy is a disease of the nervous system.
  • mononeuropathy individual nerves are affected.
  • Typical mononeuropathies are peripheral facial palsy, carpal tunnel syndrome, ulnar nerve lesion, radial nerve paresis and peroneal paresis.
  • polyneuropathy many nerves are affected simultaneously. About 3% of all people over the age of 60 suffer from polyneuropathy.
  • neuropathy may affect motor, sensory or autonomic nerves.
  • peripheral polyneuropathy There are two main forms: peripheral polyneuropathy and autonomic polyneuropathy.
  • Peripheral polyneuropathy affects the nervous system which can be influenced by the will, for example the nerves which are responsible for the sense of touch (sensible) or the muscular movement (motor). Overall, impairments of the sensory nerve fibers, which conduct information from the periphery to the spinal cord and brain, are observed earlier and more pronounced. The motor nerves, which are responsible for the movement of the muscles, can also be affected. Muscle cramps are common, massive paralysis rather rare.
  • Autonomic polyneuropathy affects the involuntary, non-willed nervous system (sympathetic and parasympathetic). For example, this autonomic nervous system regulates the changing pace of the heartbeat or gastrointestinal movements during digestion. Up to 50 percent of diabetics suffer from autonomic polyneuropathy after 20 years of illness. The symptoms depend on which organs of the body are affected:
  • the disease can affect both the isolation of the nerve (myelin) and the cell process (axon). Symmetrical and asymmetrical shapes can occur.
  • the Symptoms vary depending on the nerve fiber type and body region involved. Since the cell bodies (somata) of the sensory nerve cells in the ganglia are close to the spinal cord and the nerve processes are supplied from there, the longest nerve fibers, which have to be supplied to the toes by the organism, are most likely to be damaged. Often the disease begins with unpleasant sensations in the toes. As the disease progresses, patients often describe the distribution of discomfort as "glove-shaped" or "sock-shaped". The affected areas of the body may be tingling and uncomfortably disturbed by numbness, heavier forms may manifest themselves in polyneuropathic pain, which is often felt as burning pain. There may also be false sensations, such as cold, heat or swelling feeling occur.
  • the signs and symptoms of polyneuropathy can be divided into three groups: (i) small-fiber sensory (eg burning pain, cutaneous hyperesthesia, praesthesia, lancing pain, loss of pain and temperature perception, loss of visceral pain sensation, foot ulceration), (ii ) Large-fiber sensory (eg loss of vibration perception, ataxia due to loss of propioception, loss of reflexes, slowed nerve conduction velocity) and (iii) autonomic (eg, arrhythmia, resting tachycardia, loss of adequate heart rate adjustment, silent heart attacks, congestive heart failure, orthostatic hypotension, gustatory sweating , Hyperthermia, gastroparesis, neuropathic diarrhea, constipation, bladder dysfunction, erectile dysfunction, retrograde ejaculation).
  • small-fiber sensory eg burning pain, cutaneous hyperesthesia, praesthesia, lancing pain, loss of pain and temperature perception, loss of visceral pain sensation, foot ulceration
  • Large-fiber sensory eg loss of vibration perception,
  • NNT values N umber's Needed to T reat ⁇ number of patients who need to be treated with the drug in order for a patient to experience more than 50% pain relief
  • Diabetic polyneuropathy active substance NNT imipramine 1.4 other tricyclic antidepressants 2.4 Oextromethorphan 1.9 carbamazepine 3.3 L-Dopa 3.4 tramadol 3.4 gabapentin 3.7 capsaicin 5.9
  • Postherpetic neuralgia tricyclic antidepressants 2.3 oxycodone 2.5 gabapentin 3.2 capsaicin 5.3 (see. SH Sindrup et al., Pain, 1999, 83, 389-400 ).
  • the effectiveness of a drug in the treatment of pain can in principle be expressed in several ways. In addition to alleviating the pain on a pain scale, sometimes an increase in the average pain threshold and / or a reduction in the number of pain-sensitive pressure points ( tender points ) can be observed, which is particularly advantageous.
  • the object of the invention is to provide medicaments which have advantages over conventional medicaments.
  • the medicinal products should enable the treatment of polyneuropathic pain and thereby provide as much pain relief as possible with the least possible side effects.
  • the active ingredient 3- (2-dimethylaminomethylcyclohexyl) phenol in particular its (1R, 2R) stereoisomer, or their pharmaceutically acceptable salts, show excellent activity in the relief of polyneuropathic pain.
  • the efficacy of (1R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol in polyneuropathic pain in the animal model is about four times greater than mononeuropathic pain. Because the active ingredient shows only minor side effects, thereby therapy options are opened, which have significant advantages over conventional treatment methods.
  • the invention relates to the use of the active ingredient 3- (2-dimethylaminomethylcyclohexyl) phenol or one of its pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for the treatment of polyneuropathic pain.
  • Another aspect of the invention relates to 3- (2-dimethylaminomethylcyclohexyl) phenol or one of its pharmaceutically acceptable salts for the treatment of polyneuropathic pain.
  • the active agent is in the form of the (1R, 2R) stereoisomer, i. as (1R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol (faxeladol).
  • the other stereoisomers i. (1R, 2S), (1S, 2R) and (1S, 2S) are suitable.
  • the active ingredient may be present as a free base or as a pharmaceutically acceptable salt.
  • Preferred pharmaceutically acceptable salts are salts of inorganic acids, for example the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, hydrogen phosphate and phosphate; and organic acid salts, eg, methanesulfonate, hexane-1-sulfonate, formate, acetate, oxalate, succinate, malate, tartrate, mandelate, fumarate, maleate, lactate, citrate, glutamate, saccharinate, sebacinate, monomethyl sebacinate, 5-oxo-prolinate , Nicotinate, benzoate, aminobenzoate, methylbenzoate, trimethylbenzoate, ⁇ -liponate, N-acetylglycinate, N-acetylalaninate, N-acetylcysteinate, N-acetylisoleucinate,
  • the active ingredient is formulated in a pharmaceutical composition.
  • the pharmaceutical composition of the invention may e.g. be firm, pasty or liquid.
  • it contains pharmaceutically acceptable excipients, for example fillers, binders, solvents, lubricants and / or disintegrants.
  • suitable auxiliaries are known to the person skilled in the art. In this connection, for example, reference may be made to H.P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and adjacent areas, Editio Cantor Aulendorf.
  • the active ingredient content of the pharmaceutical composition is in the range of 0.001 to 99.999 wt%, more preferably 0.1 to 95 wt%, even more preferably 1.0 to 80 wt%, most preferably 2.5 to 65 wt%. % and in particular 5.0 to 50% by weight, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition according to the invention may optionally contain further active ingredients which may be selected, for example, from the group consisting of selective serotonin and norepinephrine reuptake inhibitors, ⁇ 2 ⁇ ligands, tricyclic Antidepressants, opioids and other analgesics.
  • further active ingredients which may be selected, for example, from the group consisting of selective serotonin and norepinephrine reuptake inhibitors, ⁇ 2 ⁇ ligands, tricyclic Antidepressants, opioids and other analgesics.
  • a COX II inhibitor is not simultaneously contained, preferably no further active ingredient at all.
  • Another aspect of the invention relates to a pharmaceutical composition as described above for the treatment of polyneuropathic pain.
  • the pharmaceutical composition is present as a dosage form.
  • the dosage form according to the invention can be, for example, solid, pasty or liquid.
  • the dosage form according to the invention is formulated for systemic, parenteral, topical or local administration.
  • the dosage form according to the invention is formulated for oral or buccal administration.
  • other forms of administration are also possible, for example for buccal, sublingual, transmucosal, rectal, intralumbar, intraperitoneal, transdermal, intravenous, intramuscular, intragluteal, intracutaneous and subcutaneous administration.
  • the dosage form preferably contains suitable additives and / or auxiliaries.
  • suitable additives and / or auxiliaries in the context of the invention are all substances known to the person skilled in the art from the prior art for achieving galenic formulations.
  • the choice of these excipients and the amounts to be used depend on how the dosage form is to be administered, i. oral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal or local.
  • preparations in the form of tablets, chewable tablets, dragées, capsules, granules, drops, juices or syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays.
  • parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays are suitable.
  • suppositories for rectal use are examples of suitable percutaneous administration forms.
  • the dosage form may be in the form of a simple tablet and a coated tablet (e.g., a coated tablet or dragee).
  • the tablets are usually round and biconvex, but oblong forms are also possible.
  • Granules, spheroids, pellets or microcapsules filled in sachets or capsules or compressed into disintegrating tablets are also possible.
  • excipients and additives for the oral administration forms are disintegrants, lubricants, binders, fillers, mold release agents, optionally solvents, flavorings, sugars, in particular vehicles, diluents, dyes, antioxidants, etc.
  • Waxes or fatty acid esters and for parenteral application agents carriers, preservatives, suspension aids, etc. can be used.
  • Excipients may be, for example: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose , Methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic gums, acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, Peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and -propy
  • a solid formulation such as a tablet
  • the active ingredient of the drug with a pharmaceutical carrier, e.g. conventional tablet ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, e.g. Water, granulated to form a solid composition containing the active ingredient in a homogeneous distribution.
  • a homogeneous distribution is understood here to mean that the active ingredient is distributed uniformly over the entire composition, so that it can be readily subdivided into equally effective unit dose forms, such as tablets, capsules, dragees.
  • the solid composition is then subdivided into unit dose forms.
  • the tablets or pills may also be coated or otherwise compounded to provide a sustained release dosage form.
  • Suitable coating agents are i.a. polymeric acids and mixtures of polymeric acids with materials such as e.g. Shellac, cetyl alcohol and / or cellulose acetate.
  • the dosage form according to the invention is formulated for one, two or three times daily administration.
  • Delayed release of the active ingredient can be achieved, for example, by retarding with the aid of a matrix, a coating or osmotic-release systems (cf., for example, US Pat WO 2005/009329 ).
  • the dosage form according to the invention sets at least 5% by weight, more preferably at least 10% by weight, more preferably at least 15% by weight, most preferably at least 20% by weight and especially at least 25% by weight. of the active substance originally contained in the dosage form.
  • the dosage form according to the invention sets under in vitro conditions after 1 h at most 95% by weight, more preferably at most 90% by weight, even more preferably at most 85% by weight, most preferably at most 80% by weight and especially at most 75% by weight of the active substance originally contained in the dosage form. Suitable methods for determining the in vitro release rate are known to the person skilled in the art.
  • the determination under sink conditions at 75 U / min in a buffer (according to Ph. Eur.) At a pH of 6.8 at 37 ° C and under UV spectroscopic detection using a Blattrühepparatur or Drehkörbchenmethode.
  • the dosage form according to the invention preferably contains the active ingredient in a dosage in the range from 1.0 to 1000 mg, more preferably 5.0 to 900 mg, even more preferably 10 to 800 mg, most preferably 15 to 700 mg and in particular 20 to 600 mg, in each case on the free base.
  • Another aspect of the invention relates to a dosage form as described above for the treatment of polyneuropathic pain.
  • the active ingredient 3- (2-dimethylaminomethylcyclohexyl) phenol and its pharmaceutically acceptable salts are suitable for the treatment of polyneuropathic pain.
  • the pain is peripheral polyneuropathic pain or central polyneuropathic pain.
  • Polyneuropathy or polyneuropathic pain is preferably acute (up to four weeks), subacute (four to eight weeks) or chronic (more than eight weeks).
  • the motor, sensory, autonomous, sensorimotor or central nervous system is preferably affected.
  • the symptoms are distributed symmetrically or asymmetrically.
  • the pain can be mild, moderate, moderate, strong or very strong.
  • the neuropathic pain scale (NPS) can serve as a measure (cf. BS Galer et al., Neurology 1997, 48, 332-8 ).
  • causes of peripheral polyneuropathic pain are diabetic polyneuropathy, postherpetic neuralgia, radioculopathy, posttraumatic neuralgia, by chemical substances, e.g. Chemotherapy-induced polyneuropathy, phantom limb pain, complex regional syndrome, HIV-induced sensory polyneuropathy, and alcoholic polyneuropathy.
  • causes of central polyneuropathic pain include compressive myelopathy due to narrowed canal stenosis, posstraumatic spinal pain, stroke pain, postischemic myelopathy, radiation-induced myelopathy, multiple sclerosis-induced myelopathism, and HIV-induced myelopathy.
  • the polyneuropathic pain causing polyneuropathy is associated with a disease selected from the group consisting of diabetes, diabetes mellitus, vasculitis, uremia, hypotyrodism, alcohol abuse, postherpetic neuralgia, idiopathic neuropathy, chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, hereditary Polyneuropathy, Guillain-Barrä syndrome, intoxication [eg by alcohol, heavy metals ⁇ especially Pb, Hg, As ⁇ , hydrocarbons, as a result of chemotherapy with cytostatics], porphyria, infectious diseases, cancers [eg myeloma, amyloid, leukemia, lymphoma], pernicious Anemia, vitamin E deficiency, Refsum disease, Basse-Kornzweig syndrome, Fabry disease, vasculitis and amyloidosis.
  • a disease selected from the group consisting of diabetes, diabetes mellitus, vasculitis, uremia, hypo
  • Diabetic polyneuropathy and postherpetic neuralgia are particularly preferred. If it is an infectious disease, it is preferably selected from the group consisting of mononucleosis, ehrlichiosis, typhus, diphtheria, leprosy, HIV, syphilis and Lyme disease.
  • the polyneuropathic pain is preferably pain which has as its cause a polyneuropathy within the meaning of ICD-10 (International Statistical Classification of Diseases and Related Health Problems, WHO edition, preferably as of 2008).
  • Polyneuropathy is preferably selected from paraneoplastic polyneuropathy, hereditary and idiopathic neuropathy [G60], polyneuritis [G61], other polyneuropathies [G62], polyneuropathy in diseases classified elsewhere [G63], neuralgia or the like. [M79.2-], Neuritis o.n.A. [M79.2-], peripheral neuritis during pregnancy [026.83] and radiculitis o.n.A. [M54.1-].
  • hereditary or idiopathic neuropathy is preferably selected from the group consisting of hereditary sensorimotor neuropathy [G60.0] (Charcot-Marie-Tooth-Hoffmann syndrome, Dejerine-Sottas disease, hereditary sensorimotor Neuropathy, type I-IV, hypertrophic neuropathy of infancy, peroneal muscle atrophy (axonal type) (hypertrophic form), Roussy-Lévy syndrome); Refsum disease [G60.1]; Neuropathy associated with hereditary ataxia [G60.2]; idiopathic progressive neuropathy [G60.3]; other hereditary and idiopathic neuropathy [G60.8] (Morvan disease, Nélaton syndrome, sensory neuropathy: dominant inheritance or recessive inheritance); and hereditary and idiopathic neuropathy, unspecified [G60.9].
  • G60.0 Hereditary sensorimotor neuropathy
  • G60.0 Charge-Marie-Tooth-Hoffmann syndrome, Dejerine-Sott
  • polyneuritis are preferably selected from the group consisting of Guillain-Barré syndrome (polyradiculoneuropathy) [G61.0] (acute (post-) infectious polyneuritis); Serum polyneuropathy [G61.1], other polyneuritides [G61.8] and polyneuritis, unspecified [G91.9].
  • polyneuropathy In the case of other polyneuropathy [G62], it is preferably selected from the group consisting of drug-induced polyneuropathy [G62.0], alcoholic polyneuropathy [G62.1], polyneuropathy by other toxic agents [G62.2], others Specified polyneuropathy [G62.8] (radiation-induced polyneuropathy, critical illness polyneuropathy [G62.80], other specified polyneuropathy [G62.88]) and polyneuropathy, unspecified [G62.9] (neuropathy NOS).
  • polyneuropathy in diseases classified elsewhere [G63] it is preferably selected from the group consisting of polyneuropathy in infectious and parasitic diseases classified elsewhere [G63.0] (polyneuropathy in: diphtheria [A36.8 ⁇ ], infectious Mononucleosis [B27. ⁇ ], leprosy [A30. ⁇ ], Lyme disease [A69.2 ⁇ ], mumps [B26.8 ⁇ ], zoster [B02.2 ⁇ ], late syphilis [A52.1 ⁇ ], late syphilis .
  • the polyneuropathic pain is associated with diabetic polyneuropathy [G63.2]. More than half of all diabetics develop nerve damage (polyneuropathy) if they have been suffering from diabetes for more than ten years. If you take all type 1 and type 2 diabetics together, about 30 percent suffer from it.
  • the polyneuropathic pain is induced by toxic agents (chemically induced polyneuropathy), preferably by drugs (e.g., chemotherapeutics) [G62.0] or alcohol [G62.1].
  • toxic agents chemically induced polyneuropathy
  • drugs e.g., chemotherapeutics
  • G62.0 chemotherapeutics
  • alcohol G62.1
  • chemotherapeutics e.g., chemotherapeutics
  • Various toxic agents are known which can induce polyneuropathy. Examples of drugs are cisplatin, didanosine, stavudine and zalcitabine.
  • mice Male Sprague Dawley rats (140-180 g, Janvier, France) were placed under standard conditions (6:00 am-6: 00 pm light, 6:00 pm-6: 00 pm, 20-24 ° C room temperature, 35-70% relative humidity, tap water and standard diet (ad libitum) in groups of five animals in Macrolon type 4 cages.
  • Inhibition of cold allodynia at each time point of measurement was expressed as the percent pretreatment (% MPE) effect, with the pretest corresponding to 0% MPE and complete inhibition (0 eviction responses per 2 min) to 100% MPE.
  • the significance of a substance effect was determined on the basis of the percent inhibition values against the vehicle group by means of two-factorial analysis of variance and post hoc analysis according to Bonferroni, the ED 50 value via linear regression analysis for the individual measurement points or the area under the curve (AUC).
  • Rats were treated with vehicle (0.9% NaCl) or vincristine (200 ⁇ g / kg iv) (1 ml / kg) on five days (day 4, 6, 8, 10, 12) resulting in a cumulative vincristine dose of 1 mg / kg.
  • vehicle 0.9% NaCl
  • vincristine 200 ⁇ g / kg iv
  • ml / kg ml / kg
  • the animals had a hypersensitivity developed against cold (cold allodynia), which lasted over a period of three weeks.
  • the animals were placed under a plastic hood on a grid and after Habituation the cold allodynia was quantified. To do this, one drop of acetone (10 ⁇ l) was carefully applied to a hind paw using a syringe and a thin plastic tube.
  • the number of induced pull-out reactions was recorded over a period of 30 seconds.
  • the cumulative number of 5 stimulations was determined before and at various times after drug or vehicle delivery.
  • the significance of a substance effect was determined on the basis of the percentage inhibition values against the vehicle group by means of two-factorial analysis of variance and post hoc analysis according to Bonferroni, the ED 50 value via linear regression analysis for the individual measurement points.
  • the ED 50 value at the same time after administration (30 min) in the polyneuropathic pain model is 5.7 mg / kg ip and in the mononeuropathic pain model is 17.6 mg / kg ip, ie approximately one factor in the polyneuropathic pain model 3 is more effective.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Use of an active ingredient, 3-(2-dimethylaminomethyl-cyclohexyl)-phenol, or its salts to prepare a pharmaceutical composition for treating polyneuropathic pain, is claimed. ACTIVITY : Analgesic. MECHANISM OF ACTION : None given.

Description

Die Erfindung betrifft die Behandlung von polyneuropathischem Schmerz, insbesondere bei diabetischer Polyneuropathie oder chemisch induzierter Polyneuropathie, durch Verabreichung von 3-(2-Dimethylaminomethyl-cyclohexyl)-phenol, vorzugsweise von (1 R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol, oder einem seiner pharmazeutisch verträglichen Salze.The invention relates to the treatment of polyneuropathic pain, in particular in diabetic polyneuropathy or chemically induced polyneuropathy, by administration of 3- (2-dimethylaminomethylcyclohexyl) phenol, preferably of (1R, 2R) -3- (2-dimethylaminomethylcyclohexyl ) -phenol, or one of its pharmaceutically acceptable salts.

Unter Neuropathie versteht man eine Erkrankung des Nervensystems. Bei der Mononeuropathie sind einzelne Nerven betroffen. Typische Mononeuropathien sind periphere Fazialisparese, Karpaltunnelsyndrom, Ulnarisläsion, Radialisparese und Peronäusparese. Bei der Polyneuropathie sind hingegen viele Nerven gleichzeitig betroffen. Etwa 3% aller Menschen über 60 Jahren leiden unter einer Polyneuropathie.Neuropathy is a disease of the nervous system. In mononeuropathy, individual nerves are affected. Typical mononeuropathies are peripheral facial palsy, carpal tunnel syndrome, ulnar nerve lesion, radial nerve paresis and peroneal paresis. In polyneuropathy, however, many nerves are affected simultaneously. About 3% of all people over the age of 60 suffer from polyneuropathy.

In Abhängigkeit von der jeweiligen Ursache können bei der Polyneuropathie motorische, sensible oder auch vegetative Nerven betroffen sein.Depending on the particular cause, neuropathy may affect motor, sensory or autonomic nerves.

Es gibt zwei Hauptformen: periphere Polyneuropathie und autonome Polyneuropathie.There are two main forms: peripheral polyneuropathy and autonomic polyneuropathy.

Die periphere Polyneuropathie betrifft das durch den Willen beeinflussbare Nervensystem, beispielsweise die Nerven, die für den Tastsinn (sensibel) oder die Muskelbewegung (motorisch) verantwortlich sind. Insgesamt sind Beeinträchtigungen der sensiblen Nervenfasern, die Informationen von der Peripherie zu Rückenmark und Gehirn leiten, früher und ausgeprägter zu beobachten. Die motorischen Nerven, die für die Bewegung der Muskeln verantwortlich sind, können aber auch betroffen sein. Muskelkrämpfe sind häufig, massive Lähmungen eher selten.Peripheral polyneuropathy affects the nervous system which can be influenced by the will, for example the nerves which are responsible for the sense of touch (sensible) or the muscular movement (motor). Overall, impairments of the sensory nerve fibers, which conduct information from the periphery to the spinal cord and brain, are observed earlier and more pronounced. The motor nerves, which are responsible for the movement of the muscles, can also be affected. Muscle cramps are common, massive paralysis rather rare.

Die autonome Polyneuropathie zieht das unwillkürliche, nicht dem eigenen Willen gehorchende Nervensystem (Sympathikus und Parasympathikus) in Mitleidenschaft. Dieses vegetative Nervensystem reguliert beispielsweise das wechselnde Tempo des Herzschlags oder die Magen-Darmbewegungen bei der Verdauung. Bis zu 50 Prozent der Diabetiker leiden nach 20-jähriger Krankheit an einer autonomen Polyneuropathie. Die Beschwerden sind davon abhängig, welche Organe des Körpers betroffen sind:Autonomic polyneuropathy affects the involuntary, non-willed nervous system (sympathetic and parasympathetic). For example, this autonomic nervous system regulates the changing pace of the heartbeat or gastrointestinal movements during digestion. Up to 50 percent of diabetics suffer from autonomic polyneuropathy after 20 years of illness. The symptoms depend on which organs of the body are affected:

Die Erkrankung kann sowohl die Isolierung des Nerven (Myelin) als auch den Zellfortsatz (Axon) betreffen. Es können symmetrische und asymmetrische Formen auftreten. Die Symptome sind je nach betroffenem Nervenfasertyp und Körperregion vielfältig. Da die Zellkörper (Somata) der sensiblen Nervenzellen in den Ganglien nahe am Rückenmark liegen und die Nervenfortsätze von dort aus versorgt werden, nehmen die längsten Nervenfasern, welche bis in die Zehen vom Organismus versorgt werden müssen, am ehesten Schaden. Häufig beginnt die Erkrankung mit unangenehmen Missempfindungen in den Zehen. Schreitet die Erkrankung fort, so wird die Verteilung der Missempfindungen von den Patienten häufig als "handschuh-" bzw. "sockenförmig" beschrieben. Die betroffenen Körperbereiche können kribbeln und unangenehm störend taub sein, schwerere Formen äußern sich in polyneuropathischem Schmerz, welcher häufig als brennender Schmerz empfunden wird. Es können ferner Fehlempfindungen, wie z.B. Kälte-, Hitze- oder Schwellungsgefühl auftreten.The disease can affect both the isolation of the nerve (myelin) and the cell process (axon). Symmetrical and asymmetrical shapes can occur. The Symptoms vary depending on the nerve fiber type and body region involved. Since the cell bodies (somata) of the sensory nerve cells in the ganglia are close to the spinal cord and the nerve processes are supplied from there, the longest nerve fibers, which have to be supplied to the toes by the organism, are most likely to be damaged. Often the disease begins with unpleasant sensations in the toes. As the disease progresses, patients often describe the distribution of discomfort as "glove-shaped" or "sock-shaped". The affected areas of the body may be tingling and uncomfortably disturbed by numbness, heavier forms may manifest themselves in polyneuropathic pain, which is often felt as burning pain. There may also be false sensations, such as cold, heat or swelling feeling occur.

Die Zeichen und Symptome der Polyneuropathie können in drei Gruppen unterteilt werden: (i) Small-Fiber sensorisch (z.B. brennende Schmerzen, cutane Hyperästhesie, Praästhesien, Lanzierende Schmerzen, Verlust der Schmerz- und Temperaturwahrnehmung, Verlust des viszeralen Schmerzempfindens, Fußulzeration), (ii) Large-Fiber sensorisch (z.B. Verlust der Vibrationswahrnehmung, Ataxie durch Verlust der Propiozeption, Verlust der Reflexe, verlangsamte Nervenleitgeschwindigkeit) und (iii) autonomisch (z.B. Herzrythmusstörungen, Ruhetachykardie, Verlust der adäquaten Herzfrequenzanpassung, stumme Herzinfarkte, Herzinsuffizienz, orthostatische Hypotension, gustatorisches Schwitzen, Hyperthermie, Gastroparese, neuropathischer Durchfall, Obstipation, Blasendysfunktion, erektile Dysfunktion, retrograde Ejakulation).The signs and symptoms of polyneuropathy can be divided into three groups: (i) small-fiber sensory (eg burning pain, cutaneous hyperesthesia, praesthesia, lancing pain, loss of pain and temperature perception, loss of visceral pain sensation, foot ulceration), (ii ) Large-fiber sensory (eg loss of vibration perception, ataxia due to loss of propioception, loss of reflexes, slowed nerve conduction velocity) and (iii) autonomic (eg, arrhythmia, resting tachycardia, loss of adequate heart rate adjustment, silent heart attacks, congestive heart failure, orthostatic hypotension, gustatory sweating , Hyperthermia, gastroparesis, neuropathic diarrhea, constipation, bladder dysfunction, erectile dysfunction, retrograde ejaculation).

Je nach betroffenem Nervenfasertyp kann man folgende Modalitäten unterscheiden:

  • Fasertyp A-α (I) (13-20 µm, myelinisiert): Propriozeption der Gliedmaßen;
  • Fasertyp A-β (II) (6-12 µm, myelinisiert): Propriozeption der Gliedmaßen, Vibration, Druck;
  • Fasertyp A-δ (III) (1-5 µm, myelinisiert): mechanischer, scharfer, stechender Schmerz, intensiver Druck auf die Haut (über mechanische Nociceptoren) und extreme Temperatur (über thermische Nociceptoren);
  • Fasertyp C (IV) (0,2-1,5 µm, unmyelinisiert): brennender, andauernder, diffuser Schmerz, temperaturausgelöster Schmerz, mechanischer brennender Schmerz über polymodale Nociceptoren bei hoher Intensität der thermalen bzw. chemischen Stimuli.
Depending on the type of nerve fiber affected, the following modalities can be distinguished:
  • Fiber type A-α (I) (13-20 μm, myelinated): Proprioception of the limbs;
  • Fiber type A-β (II) (6-12 μm, myelinated): Proprioception of the limbs, vibration, pressure;
  • Fiber type A-δ (III) (1-5 μm, myelinated): mechanical, sharp, stabbing pain, intense pressure on the skin (via mechanical nociceptors) and extreme temperature (via thermal nociceptors);
  • Fiber type C (IV) (0.2-1.5 μm, unmyelinated): burning, persistent, diffuse pain, temperature-triggered pain, mechanical burning pain over polymodal nociceptors at high intensity of thermal or chemical stimuli.

Eine zufrieden stellende Bekämpfung der Schmerzen bei Polyneuropathie durch Verabreichung herkömmlicher Analgetika nur eingeschränkt möglich ( H. Chen et al., Mayo Clin Proc. 2004, 79, 1533-45 ; M. Namaka et al., Clin Ther. 2004, 26, 951-79 ). Plazebokontrollierte Studien zur medikamentösen Behandlung der Schmerzen bei Polyneuropathie haben folgende NNT-Werte ergeben ( Numbers Needed to Treat ≡ Anzahl der Patienten, die mit dem jeweiligen Medikament behandelt werden müssen, damit ein Patient eine mehr als 50%ige Schmerzlinderung erfährt): Diabetische Polyneuropathie Wirkstoff NNT Imipramin 1,4 andere tricyclische Antidepressiva 2,4 Oextromethorphan 1,9 Carbamazepin 3,3 L-Dopa 3,4 Tramadol 3,4 Gabapentin 3,7 Capsaicin 5,9 selektive Serotonin Wiederaufnahme Inhibitoren 6,7 Mexiletin 10,0 Postherpetische Neuralgie tricyclische Antidepressiva 2,3 Oxycodon 2,5 Gabapentin 3,2 Capsaicin 5,3 (vgl. S.H. Sindrup et al., Pain, 1999, 83, 389-400 ).Satisfactory control of pain in polyneuropathy by administration of conventional analgesics limited possible ( H. Chen et al., Mayo Clin Proc. 2004, 79, 1533-45 ; Namaka, M., et al., Clin Ther. 2004, 26, 951-79 ). Placebo-controlled studies on the treatment of pain in polyneuropathy have shown the following NNT values ( N umber's Needed to T reat ≡ number of patients who need to be treated with the drug in order for a patient to experience more than 50% pain relief): Diabetic polyneuropathy active substance NNT imipramine 1.4 other tricyclic antidepressants 2.4 Oextromethorphan 1.9 carbamazepine 3.3 L-Dopa 3.4 tramadol 3.4 gabapentin 3.7 capsaicin 5.9 Selective serotonin reuptake inhibitors 6.7 mexiletine 10.0 Postherpetic neuralgia tricyclic antidepressants 2.3 oxycodone 2.5 gabapentin 3.2 capsaicin 5.3 (see. SH Sindrup et al., Pain, 1999, 83, 389-400 ).

Die Wirksamkeit eines Arzneistoffs bei der Behandlung von Schmerz kann sich grundsätzlich in verschiedener Hinsicht äußern. Neben der Linderung der Schmerzen auf einer Schmerzskala kann mitunter z.B. auch eine Anhebung der durchschnittlichen Schmerzschwelle (average pain threshold) und/oder eine Verringerung der Anzahl der schmerzsensitiven Druckpunkte (tender points) beobachtet werden, was besonders vorteilhaft ist.The effectiveness of a drug in the treatment of pain can in principle be expressed in several ways. In addition to alleviating the pain on a pain scale, sometimes an increase in the average pain threshold and / or a reduction in the number of pain-sensitive pressure points ( tender points ) can be observed, which is particularly advantageous.

Der Erfindung liegt die Aufgabe zugrunde, Arzneimittel bereitzustellen, welche Vorteile gegenüber herkömmlichen Arzneimitteln haben. Die Arzneimittel sollten eine Behandlung von polyneuropathischem Schmerz ermöglichen und dabei eine möglichst große Schmerzlinderung bei möglichst geringen Nebenwirkungen bewirken.The object of the invention is to provide medicaments which have advantages over conventional medicaments. The medicinal products should enable the treatment of polyneuropathic pain and thereby provide as much pain relief as possible with the least possible side effects.

Diese Aufgabe wird durch den Gegenstand der Patentansprüche gelöst.This object is solved by the subject matter of the claims.

Es wurde überraschend gefunden, dass der Wirkstoff 3-(2-Dimethylaminomethyl-cyclohexyl)-phenol, insbesondere sein (1 R,2R)-Stereoisomer, bzw. deren pharmazeutisch verträgliche Salze eine hervorragende Wirksamkeit bei der Linderung von polyneuropathischem Schmerz zeigen. So haben experimentelle Untersuchungen ergeben, dass die Wirksamkeit von (1 R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol bei polyneuropathischen Schmerz im Tiermodell etwa viermal größer ist als bei mononeuropathischem Schmerz. Da der Wirkstoff nur geringe Nebenwirkungen zeigt, werden dadurch Therapiemöglichkeiten eröffnet, welche erhebliche Vorteile gegenüber herkömmlichen Behandlungsmethoden haben.It has surprisingly been found that the active ingredient 3- (2-dimethylaminomethylcyclohexyl) phenol, in particular its (1R, 2R) stereoisomer, or their pharmaceutically acceptable salts, show excellent activity in the relief of polyneuropathic pain. Thus, experimental studies have shown that the efficacy of (1R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol in polyneuropathic pain in the animal model is about four times greater than mononeuropathic pain. Because the active ingredient shows only minor side effects, thereby therapy options are opened, which have significant advantages over conventional treatment methods.

(1 R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol ist auch unter dem INN "Faxeladol" bekannt und hat folgende Struktur:

Figure imgb0001
(1R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol is also known under the INN "Faxeladol" and has the following structure:
Figure imgb0001

(1 R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol, einige seiner pharmazeutisch verträglichen Salze und die Verwendung zur Behandlung von bestimmten Schmerzarten sind aus dem Stand der Technik bekannt. In diesem Zusammenhang kann beispielsweise verwiesen werden auf DE-A 195 25 137 , US 5,733,936 , WO 2004/009067 , WO 2004/ 047823 und DE 10 2005 034 974 .(1R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol, some of its pharmaceutically acceptable salts, and use for the treatment of certain types of pain are known in the art. In this context, for example, reference can be made to DE-A 195 25 137 . US 5,733,936 . WO 2004/009067 . WO 2004/047823 and DE 10 2005 034 974 ,

Die Erfindung betrifft die Verwendung des Wirkstoffs 3-(2-Dimethylaminomethyl-cyclohexyl)-phenol oder eines seiner pharmazeutisch verträglichen Salze zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von polyneuropathischem Schmerz.The invention relates to the use of the active ingredient 3- (2-dimethylaminomethylcyclohexyl) phenol or one of its pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for the treatment of polyneuropathic pain.

Ein weiterer Aspekt der Erfindung betrifft 3-(2-Dimethylaminomethyl-cyclohexyl)-phenol oder eines seiner pharmazeutisch verträglichen Salze zur Behandlung von polyneuropathischem Schmerz.Another aspect of the invention relates to 3- (2-dimethylaminomethylcyclohexyl) phenol or one of its pharmaceutically acceptable salts for the treatment of polyneuropathic pain.

Vorzugsweise liegt der Wirkstoff in Form des (1R,2R)-Stereoisomers, d.h. als (1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol (Faxeladol) vor. Grundsätzlich sind aber auch die übrigen Stereoisomere, d.h. (1R,2S), (1S,2R) und (1S,2S) geeignet.Preferably, the active agent is in the form of the (1R, 2R) stereoisomer, i. as (1R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol (faxeladol). In principle, however, the other stereoisomers, i. (1R, 2S), (1S, 2R) and (1S, 2S) are suitable.

Der Wirkstoff kann als freie Base oder als pharmazeutisch verträgliches Salz vorliegen. Bevorzugte pharmazeutisch verträgliche Salze sind Salze anorganischer Säuren, z.B. das Hydrochlorid, Hydrobromid, Sulfat, Hydrogensulfat, Dihydrogenphosphat, Hydrogenphsophat und Phosphat; und Salze organischer Säuren, z.B. das Methansulfonat, Hexan-1-sulfonat, Formiat, Acetat, Oxalat, Succinat, Malat, Tartrat, Mandelat, Fumarat, Maleat, Lactat, Citrat, Glutamat, Saccharinat, Sebacinat, Monomethylsebacinat, 5-Oxo-Prolinat, Nicotinat, Benzoat, Aminobenzoat, Methylbenzoat, Trimethylbenzoat, α-Liponat, N-Acetylglycinat, N-Acetylalaninat, N-Acetylcysteinat, N-Acetylisoleucinat, N-Acetylleucinat, N-Acetylmethioninat, N-Acetylphenylalaninat, N-Acetylprolin, N-Acetylserin, N-Acetylthreonin, N-Acetyltyrosin, N-Acetylvalin, Acetylsalicylat, Acorbat, Hippurat und Asparaginat. Besonders bevorzugt liegt der Wirkstoff als Maleat vor.The active ingredient may be present as a free base or as a pharmaceutically acceptable salt. Preferred pharmaceutically acceptable salts are salts of inorganic acids, for example the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, hydrogen phosphate and phosphate; and organic acid salts, eg, methanesulfonate, hexane-1-sulfonate, formate, acetate, oxalate, succinate, malate, tartrate, mandelate, fumarate, maleate, lactate, citrate, glutamate, saccharinate, sebacinate, monomethyl sebacinate, 5-oxo-prolinate , Nicotinate, benzoate, aminobenzoate, methylbenzoate, trimethylbenzoate, α-liponate, N-acetylglycinate, N-acetylalaninate, N-acetylcysteinate, N-acetylisoleucinate, N-acetylleucinate, N-acetylmethioninate, N-acetylphenylalaninate, N-acetylproline, N-acetylserine, N-acetylthreonine, N-acetyltyrosine, N-acetylvaline, acetylsalicylate, acorbate, hippurate and asparaginate. Particularly preferably, the active ingredient is present as maleate.

Vorzugsweise ist der Wirkstoff in einer pharmazeutischen Zusammensetzung formuliert. Die erfindungsgemäße pharmazeutische Zusammensetzung kann z.B. fest, pastös oder flüssig sein. Vorzugsweise enthält sie pharmazeutisch verträgliche Hilfsstoffe, beispielsweise Füllmittel, Bindemittel, Lösungsmittel, Gleitmittel und/oder Sprengmittel. Die Wahl der jeweiligen Hilfsstoffe hängt davon ab, für welche Art der Verabreichung die pharmazeutische Zusammensetzung vorgesehen ist. Geeignete Hilfsstoffe sind dem Fachmann bekannt. In diesem Zusammenhang kann beispielsweise verwiesen werden auf H.P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendorf.Preferably, the active ingredient is formulated in a pharmaceutical composition. The pharmaceutical composition of the invention may e.g. be firm, pasty or liquid. Preferably, it contains pharmaceutically acceptable excipients, for example fillers, binders, solvents, lubricants and / or disintegrants. The choice of the particular excipients depends on the type of administration the pharmaceutical composition is intended for. Suitable auxiliaries are known to the person skilled in the art. In this connection, for example, reference may be made to H.P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and adjacent areas, Editio Cantor Aulendorf.

Vorzugsweise liegt der Wirkstoffgehalt der pharmazeutischen Zusammensetzung im Bereich von 0,001 bis 99,999 Gew.-%, bevorzugter 0,1 bis 95 Gew.-%, noch bevorzugter 1,0 bis 80 Gew.-%, am bevorzugtesten 2,5 bis 65 Gew.-% und insbesondere 5,0 bis 50 Gew.-%, bezogen auf das Gesamtgewicht der pharmazeutischen Zusammensetzung.Preferably, the active ingredient content of the pharmaceutical composition is in the range of 0.001 to 99.999 wt%, more preferably 0.1 to 95 wt%, even more preferably 1.0 to 80 wt%, most preferably 2.5 to 65 wt%. % and in particular 5.0 to 50% by weight, based on the total weight of the pharmaceutical composition.

Die erfindungsgemäße pharmazeutische Zusammensetzung kann neben 3-(2-Dimethylaminomethyl-cyclohexyl)-phenol ggf. weitere Wirkstoffe enthalten, welche beispielsweise ausgewählt sein können aus der Gruppe bestehend aus selektiven Serotonin- und Norepinephrin-Wiederaufnahme-Inhibitoren, α2δ-Liganden, tricyclischen Antidepressiva, Opioiden und anderen Analgetika. Vorzugsweise ist jedoch nicht gleichzeitig ein COX II-Inhibitor enthalten, vorzugsweise überhaupt kein weiterer Wirkstoff.In addition to 3- (2-dimethylaminomethyl-cyclohexyl) -phenol, the pharmaceutical composition according to the invention may optionally contain further active ingredients which may be selected, for example, from the group consisting of selective serotonin and norepinephrine reuptake inhibitors, α 2 δ ligands, tricyclic Antidepressants, opioids and other analgesics. Preferably, however, a COX II inhibitor is not simultaneously contained, preferably no further active ingredient at all.

Ein weiterer Aspekt der Erfindung betrifft eine wie vorstehend beschriebene pharmazeutische Zusammensetzung zur Behandlung von polyneuropathischem Schmerz.Another aspect of the invention relates to a pharmaceutical composition as described above for the treatment of polyneuropathic pain.

In einer bevorzugten Ausführungsform liegt die pharmazeutische Zusammensetzung als Darreichungsform vor. Die erfindungsgemäße Darreichungsform kann z.B. fest, pastös oder flüssig sein. Vorzugsweise ist die erfindungsgemäße Darreichungsform zur systemischen, parenteralen, topischen oder lokalen Verabreichung konfektioniert. Vorzugsweise ist die erfindungsgemäße Darreichungsform zur oralen oder buccalen Verabreichung konfektioniert. Es sind jedoch auch andere Verabreichungsformen möglich, beispielsweise zur buccalen, sublingualen, transmucosalen, rektalen, intralumbalen, intraperitonealen, transdermalen, intravenösen, intramuskulären, intraglutealen, intrakutanen und subkutanen Applikation.In a preferred embodiment, the pharmaceutical composition is present as a dosage form. The dosage form according to the invention can be, for example, solid, pasty or liquid. Preferably, the dosage form according to the invention is formulated for systemic, parenteral, topical or local administration. Preferably, the dosage form according to the invention is formulated for oral or buccal administration. However, other forms of administration are also possible, for example for buccal, sublingual, transmucosal, rectal, intralumbar, intraperitoneal, transdermal, intravenous, intramuscular, intragluteal, intracutaneous and subcutaneous administration.

Je nach Konfektionierung enthält die Darreichungsform vorzugsweise geeignete Zusatz- und/oder Hilfsstoffe. Geeignete Zusatz- und/oder Hilfsstoffe im Sinne der Erfindung sind alle dem Fachmann aus dem Stand der Technik bekannten Stoffe zur Erreichung galenischer Formulierungen. Die Auswahl dieser Hilfsstoffe sowie die einzusetzenden Mengen hängen davon ab, wie die Darreichungsform appliziert werden soll, d.h. oral, intravenös, intraperitoneal, intradermal, intramuskulär, intranasal, buccal oder lokal.Depending on the preparation, the dosage form preferably contains suitable additives and / or auxiliaries. Suitable additives and / or auxiliaries in the context of the invention are all substances known to the person skilled in the art from the prior art for achieving galenic formulations. The choice of these excipients and the amounts to be used depend on how the dosage form is to be administered, i. oral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal or local.

Für die orale Applikation eignen sich Zubereitungen in Form von Tabletten, Kautabletten, Dragees, Kapseln, Granulaten, Tropfen, Säften oder Sirupen, für die parenterale, topische und inhalative Applikation Lösungen, Suspensionen, leicht rekonstituierbare Trockenzubereitungen sowie Sprays. Eine weitere Möglichkeit sind Suppositorien zur rektalen Anwendung. Die Anwendung in einem Depot in gelöster Form, einer Trägerfolie oder einem Pflaster, gegebenenfalls unter Zusatz von die Hautpenetration fördernden Mitteln, sind Beispiele für geeignete perkutane Applikationsformen.For oral administration, preparations in the form of tablets, chewable tablets, dragées, capsules, granules, drops, juices or syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays. Another option is suppositories for rectal use. The use in a depot in dissolved form, a carrier film or a plaster, optionally with the addition of skin penetration promoting agents, are examples of suitable percutaneous administration forms.

Die Darreichungsform kann als einfache Tablette und als überzogene Tablette (z.B. als Filmtablette oder Dragee) vorliegen. Die Tabletten sind üblicherweise rund und bikonvex, oblong Formen sind jedoch ebenfalls möglich. Granulate, Sphäroide, Pellets oder Mikrokapseln, welche in Sachets oder Kapseln gefüllt oder zu zerfallenden Tabletten verpresst sind, sind ebenfalls möglich.The dosage form may be in the form of a simple tablet and a coated tablet (e.g., a coated tablet or dragee). The tablets are usually round and biconvex, but oblong forms are also possible. Granules, spheroids, pellets or microcapsules filled in sachets or capsules or compressed into disintegrating tablets are also possible.

Beispiele für Hilfs- und Zusatzstoffe für die oralen Applikationsformen sind Sprengmittel, Gleitmittel, Binder, Füllmittel, Formtrennmittel, gegebenenfalls Lösungsmittel, Geschmacksstoffe, Zucker, insbesondere Trägermittel, Verdünnungsmittel, Farbstoffe, Antioxidantien etc.Examples of excipients and additives for the oral administration forms are disintegrants, lubricants, binders, fillers, mold release agents, optionally solvents, flavorings, sugars, in particular vehicles, diluents, dyes, antioxidants, etc.

Für Suppositorien können u.a. Wachse bzw. Fettsäureester und für parenterale Applikationsmittel Trägerstoffe, Konservierungsmittel, Suspensionshilfsmittel etc. verwendet werden.For suppositories u.a. Waxes or fatty acid esters and for parenteral application agents carriers, preservatives, suspension aids, etc. can be used.

Hilfsstoffe können beispielsweise sein: Wasser, Ethanol, 2-Propanol, Glycerin, Ethylenglycol, Propylenglycol, Polyethylenglycol, Polypropylenglycol, Glucose, Fructose, Lactose, Saccharose, Dextrose, Melasse, Stärke, modifizierte Stärke, Gelatine, Sorbitol, Inositol, Mannitol, mikrokristalline Cellulose, Methylcellulose, Carboxymethylcellulose, Celluloseacetat, Schellack, Cetylalkohol, Polyvinylpyrrolidon, Paraffine, Wachse, natürliche und synthetische Gummis, Akaziengummi, Alginate, Dextran, gesättigte und ungesättigte Fettsäuren, Stearinsäure, Magnesiumstearat, Zinkstearat, Glycerylstearat, Natriumlaurylsulfat, genießbare Öle, Sesamöl, Kokusnussöl, Erdnussöl, Sojabohnenöl, Lecithin, Natriumlactat, Polyoxyethylen- und -propylenfettsäureester, Sorbitanfettsäureester, Sorbinsäure, Benzoesäure, Citronensäure, Ascorbinsäure, Tanninsäure, Natriumchlorid, Kaliumchlorid, Magnesiumchlorid, Calciumchlorid, Magnesiumoxid, Zinkoxid, Siliciumdioxid, Titanoxid, Titandioxid, Magnesiumsulfat, Zinksulfat, Calciumsulfat, Pottasche, Calciumphosphat, Dicalciumphosphat, Kaliumbromid, Kaliumiodid, Talkum, Kaolin, Pectin, Crospovidon, Agar und Bentonit.Excipients may be, for example: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose , Methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic gums, acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, Peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and -propylene fatty acid esters, sorbitan fatty acid esters, sorbic acid, benzoic acid, citric acid, Ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silica, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidone, agar and bentonite.

Die Herstellung dieser Arzneimittel und pharmazeutischen Zusammensetzungen erfolgt mit Hilfe von im Stand der Technik der pharmazeutischen Technologie wohlbekannten Mitteln, Vorrichtungen, Methoden und Verfahren, wie sie beispielsweise in " Remington's Pharmaceutical Sciences", Hrsg. A.R. Gennaro, 17. Ed., Mack Publishing Company, Easton, Pa. (1985 ), insbesondere in Teil 8, Kapitel 76 bis 93, beschrieben sind.The preparation of these pharmaceuticals and pharmaceutical compositions is effected by means well known in the art of pharmaceutical technology means, devices, methods and procedures, as described for example in " Remington's Pharmaceutical Sciences, ed. AR Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa. (1985 ), in particular in Part 8, Chapters 76 to 93.

So kann z.B. für eine feste Formulierung, wie eine Tablette, der Wirkstoff des Arzneimittels mit einem pharmazeutischen Träger, z.B. herkömmlichen Tabletteninhaltsstoffen, wie Maisstärke, Lactose, Saccharose, Sorbitol, Talkum, Magnesiumstearat, Dicalciumphosphat oder pharmazeutisch akzeptable Gummis, und pharmazeutischen Verdünnungsmitteln, wie z.B. Wasser, granuliert werden, um eine feste Zusammensetzung zu bilden, die den Wirkstoff in homogener Verteilung enthält. Unter einer homogenen Verteilung wird hier verstanden, dass der Wirkstoff gleichmäßig über die gesamte Zusammensetzung verteilt ist, so dass diese ohne weiteres in gleich wirksame Einheitsdosis-Formen, wie Tabletten, Kapseln, Dragees unterteilt werden kann. Die feste Zusammensetzung wird anschließend in Einheitsdosis-Formen unterteilt. Die Tabletten oder Pillen können auch überzogen oder auf andere Weise kompoundiert werden, um eine Dosisform mit verzögerter Freisetzung bereitzustellen. Geeignete Beschichtungsmittel sind u.a. polymere Säuren und Mischungen von polymeren Säuren mit Materialien wie z.B. Schellack, Cetylalkohol und/oder Celluloseacetat.Thus, e.g. for a solid formulation, such as a tablet, the active ingredient of the drug with a pharmaceutical carrier, e.g. conventional tablet ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, e.g. Water, granulated to form a solid composition containing the active ingredient in a homogeneous distribution. A homogeneous distribution is understood here to mean that the active ingredient is distributed uniformly over the entire composition, so that it can be readily subdivided into equally effective unit dose forms, such as tablets, capsules, dragees. The solid composition is then subdivided into unit dose forms. The tablets or pills may also be coated or otherwise compounded to provide a sustained release dosage form. Suitable coating agents are i.a. polymeric acids and mixtures of polymeric acids with materials such as e.g. Shellac, cetyl alcohol and / or cellulose acetate.

In einer bevorzugten Ausführungsform ist die erfindungsgemäße Darreichungsform zur ein-, zwei- oder dreimal täglichen Verabreichung konfektioniert.In a preferred embodiment, the dosage form according to the invention is formulated for one, two or three times daily administration.

Eine verzögerte Freisetzung des Wirkstoffs kann beispielsweise durch Retardierung mit Hilfe einer Matrix, eines Überzugs oder osmotisch wirkender Freisetzungssysteme erreicht werden (vgl. z.B. WO 2005/009329 ).Delayed release of the active ingredient can be achieved, for example, by retarding with the aid of a matrix, a coating or osmotic-release systems (cf., for example, US Pat WO 2005/009329 ).

Bevorzugt setzt die erfindungsgemäße Darreichungsform unter in vitro Bedingungen nach 1 h wenigstens 5 Gew.-%, bevorzugter wenigstens 10 Gew.%, noch bevorzugter wenigstens 15 Gew.%, am bevorzugtesten wenigstens 20 Gew.-% und insbesondere wenigstens 25 Gew.-% des ursprünglich in der Darreichungsform enthaltenen Wirkstoffs frei. Bevorzugt setzt die erfindungsgemäße Darreichungsform unter in vitro Bedingungen nach 1 h höchstens 95 Gew.-%, bevorzugter höchstens 90 Gew.-%, noch bevorzugter höchstens 85 Gew.-%, am bevorzugtesten höchstens 80 Gew.-% und insbesondere höchstens 75 Gew.-% des ursprünglich in der Darreichungsform enthaltenen Wirkstoffs frei. Geeignete Methoden zur Bestimmung der in vitro Freisetzungsrate sind dem Fachmann bekannt. Vorzugsweise erfolgt die Bestimmung unter sink Bedingungen bei 75 U/min in einem Puffer (gemäß Ph. Eur.) bei einem pH-Wert von 6,8 bei 37°C und unter UV-spektroskopischer Detektion mit Hilfe einer Blattrührapparatur oder der Drehkörbchenmethode.Preferably, under in vitro conditions, the dosage form according to the invention sets at least 5% by weight, more preferably at least 10% by weight, more preferably at least 15% by weight, most preferably at least 20% by weight and especially at least 25% by weight. of the active substance originally contained in the dosage form. Preferably, the dosage form according to the invention sets under in vitro conditions after 1 h at most 95% by weight, more preferably at most 90% by weight, even more preferably at most 85% by weight, most preferably at most 80% by weight and especially at most 75% by weight of the active substance originally contained in the dosage form. Suitable methods for determining the in vitro release rate are known to the person skilled in the art. Preferably, the determination under sink conditions at 75 U / min in a buffer (according to Ph. Eur.) At a pH of 6.8 at 37 ° C and under UV spectroscopic detection using a Blattrühepparatur or Drehkörbchenmethode.

Die erfindungsgemäße Darreichungsform enthält den Wirkstoff vorzugsweise in einer Dosierung im Bereich von 1,0 bis 1000 mg, bevorzugter 5,0 bis 900 mg, noch bevorzugter 10 bis 800 mg, am bevorzugtesten 15 bis 700 mg und insbesondere 20 bis 600 mg, jeweils bezogen auf die freie Base. Üblicherweise werden 0,1 bis 5000 mg/kg, insbesondere 1 bis 500 mg/kg, vorzugsweise 2 bis 250 mg/kg Körpergewicht verabreicht. Ebenso bevorzugt und üblich ist aber auch die Verabreichung von 0,01 bis 5 mg/kg, vorzugsweise 0,03 bis 2 mg/kg, insbesondere 0,05 bis 1 mg/kg.The dosage form according to the invention preferably contains the active ingredient in a dosage in the range from 1.0 to 1000 mg, more preferably 5.0 to 900 mg, even more preferably 10 to 800 mg, most preferably 15 to 700 mg and in particular 20 to 600 mg, in each case on the free base. Usually, 0.1 to 5000 mg / kg, in particular 1 to 500 mg / kg, preferably 2 to 250 mg / kg body weight administered. Equally preferred and customary, however, is the administration of 0.01 to 5 mg / kg, preferably 0.03 to 2 mg / kg, in particular 0.05 to 1 mg / kg.

In einer bevorzugten Ausführungsform

  • - ist die Darreichungsform zur oralen Verabreichung konfektioniert; und/oder
  • - ist die Darreichungsform eine feste und/oder verpresste und/oder filmbeschichtete Arzneiform; und/oder
  • - setzt die Darreichungsform den Wirkstoff aus einer Matrix verzögert frei; und/oder
  • - enthält die Darreichungsform den Wirkstoff in einer Menge von 0,001 bis 99,999 Gew.-%, bevorzugter 0,1 bis 99,9 Gew.-%, noch bevorzugter 1,0 bis 99,0 Gew.-%, noch bevorzugter 2,5 bis 80 Gew.-%, am bevorzugtesten 5,0 bis 50 Gew.-% und insbesondere 7,5 bis 40 Gew.-%, bezogen auf das Gesamtgewicht der Darreichungsform; und/oder
  • - enthält die Darreichungsform einen pharmazeutisch verträglichen Träger und/oder pharmazeutisch verträgliche Hilfsstoffe; und/oder
  • - weist die Darreichungsform eine Gesamtmasse im Bereich von 25 bis 2.000 mg, bevorzugter 50 bis 1.800 mg, noch bevorzugter 60 bis 1.600 mg, noch bevorzugter 70 bis 1.400 mg, am bevorzugtesten 80 bis 1.200 mg und insbesondere 100 bis 1.000 mg auf, und/oder
  • - ist die Darreichungsform ausgewählt aus der Gruppe bestehend aus Tabletten, Kapseln, Pellets und Granulaten.
In a preferred embodiment
  • - the dosage form is formulated for oral administration; and or
  • - The dosage form is a solid and / or compressed and / or film-coated dosage form; and or
  • - the dosage form releases the active substance from a matrix with a delay; and or
  • the dosage form contains the active substance in an amount of 0.001 to 99.999% by weight, more preferably 0.1 to 99.9% by weight, even more preferably 1.0 to 99.0% by weight, more preferably 2.5 up to 80% by weight, most preferably 5.0 to 50% by weight and in particular 7.5 to 40% by weight, based on the total weight of the dosage form; and or
  • - contains the dosage form a pharmaceutically acceptable carrier and / or pharmaceutically acceptable excipients; and or
  • the dosage form has a total mass in the range from 25 to 2,000 mg, more preferably 50 to 1,800 mg, even more preferably 60 to 1,600 mg, even more preferably 70 to 1,400 mg, most preferably 80 to 1,200 mg and especially 100 to 1,000 mg, and / or
  • - The dosage form is selected from the group consisting of tablets, capsules, pellets and granules.

Ein weiterer Aspekt der Erfindung betrifft eine wie vorstehend beschriebene Darreichungsform zur Behandlung von polyneuropathischem Schmerz.Another aspect of the invention relates to a dosage form as described above for the treatment of polyneuropathic pain.

Der Wirkstoff 3-(2-Dimethylaminomethyl-cyclohexyl)-phenol und seine pharmazeutisch verträglichen Salze eignet sich zur Behandlung von polyneuropathischem Schmerz. Bevorzugt ist der Schmerz peripherer polyneuropathischer Schmerz oder zentraler polyneuropathischer Schmerz. Bevorzugt ist die Polyneuropathie bzw. der polyneuropathische Schmerz akut (bis vier Wochen), subakut (vier bis acht Wochen) oder chronisch (mehr als acht Wochen). Bevorzugt ist bei der Polyneuropathie das motorische, sensible, autonome, sensomotorische oder zentrale Nervensystem betroffen. Vorzugsweise sind die Symptome symmetrisch oder asymmetrisch verteilt. Der Schmerz kann leicht, mäßig, mittelstark, stark oder sehr stark sein. Als Maß kann die neuropathische Schmerzskala (NPS) dienen (vgl. B.S. Galer et al., Neurology 1997, 48, 332-8 ).The active ingredient 3- (2-dimethylaminomethylcyclohexyl) phenol and its pharmaceutically acceptable salts are suitable for the treatment of polyneuropathic pain. Preferably, the pain is peripheral polyneuropathic pain or central polyneuropathic pain. Polyneuropathy or polyneuropathic pain is preferably acute (up to four weeks), subacute (four to eight weeks) or chronic (more than eight weeks). In the case of polyneuropathy, the motor, sensory, autonomous, sensorimotor or central nervous system is preferably affected. Preferably, the symptoms are distributed symmetrically or asymmetrically. The pain can be mild, moderate, moderate, strong or very strong. The neuropathic pain scale (NPS) can serve as a measure (cf. BS Galer et al., Neurology 1997, 48, 332-8 ).

Beispiele für Ursachen von peripherem polyneuropathischem Schmerz sind diabetische Polyneuropathie, postherpetische Neuralgie, Radioculopathie, posttraumatische Neuralgie, durch chemische Substanzen, z.B. durch Chemotherapie induzierte Polyneuropathie, Phantomschmerzen an den Gliedmaßen, komplexes regionales Syndrom, HIV-induzierte sensorische Polyneuropathie und alkoholische Polyneuropathie. Beispiele für Ursachen von zentralem polyneuropathischem Schmerz sind kompressive Myelopathie infolge von verengter Kanalstenose, posstraumatischer Spinalschmerz, Schlaganfallschmerz, postischemische Myelopathie, strahleninduzierte Myelopathie, durch Multiple Sklerose induzierte Myelopahthie und HIV-induzierte Myelopathie.Examples of causes of peripheral polyneuropathic pain are diabetic polyneuropathy, postherpetic neuralgia, radioculopathy, posttraumatic neuralgia, by chemical substances, e.g. Chemotherapy-induced polyneuropathy, phantom limb pain, complex regional syndrome, HIV-induced sensory polyneuropathy, and alcoholic polyneuropathy. Examples of causes of central polyneuropathic pain include compressive myelopathy due to narrowed canal stenosis, posstraumatic spinal pain, stroke pain, postischemic myelopathy, radiation-induced myelopathy, multiple sclerosis-induced myelopathism, and HIV-induced myelopathy.

In einer bevorzugten Ausführungsform ist die den polyneuropathischen Schmerz verursachende Polyneuropathie assoziiert mit einer Erkrankung ausgewählt aus der Gruppe bestehend aus Diabetes, Diabetes mellitus, Vaskulitis, Urämie, Hypotyrodismus, Alkoholmissbrauch, postherpetischer Neuralgie, idiopathischer Neuropahthie, chronisch entzündlicher demyelinisierender Neuropathie, multifokaler motorischer Neuropathie, hereditärer Polyneuropathie, Guillain-Barrä-Syndrom, Intoxikation [z.B. durch Alkohol, Schwermetalle {insbesondere Pb, Hg, As}, Hydrocarbone, infolge einer Chemotherapie mit Cytostatika], Porphyrie, Infektionskrankheiten, Krebserkrankungen [z.B. Myelom, Amyloid, Leukämie, Lymphome], perniziöse Anämie, Vitamin-E-Mangel, Morbus Refsum, Bassen-Kornzweig-Syndrom, Morbus-Fabry, Vaskulitis und Amyloidose. Diabetische Polyneuropathie und postherpetische Neuralgie sind besonders bevorzugt. Handelt es sich um eine Infektionskrankheit, so ist diese vorzugsweise ausgewählt aus der Gruppe bestehend aus Mononukleose, Ehrlichiose, Typhus, Diphterie, Lepra, HIV, Lues und Borreliose.In a preferred embodiment, the polyneuropathic pain causing polyneuropathy is associated with a disease selected from the group consisting of diabetes, diabetes mellitus, vasculitis, uremia, hypotyrodism, alcohol abuse, postherpetic neuralgia, idiopathic neuropathy, chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, hereditary Polyneuropathy, Guillain-Barrä syndrome, intoxication [eg by alcohol, heavy metals {especially Pb, Hg, As}, hydrocarbons, as a result of chemotherapy with cytostatics], porphyria, infectious diseases, cancers [eg myeloma, amyloid, leukemia, lymphoma], pernicious Anemia, vitamin E deficiency, Refsum disease, Basse-Kornzweig syndrome, Fabry disease, vasculitis and amyloidosis. Diabetic polyneuropathy and postherpetic neuralgia are particularly preferred. If it is an infectious disease, it is preferably selected from the group consisting of mononucleosis, ehrlichiosis, typhus, diphtheria, leprosy, HIV, syphilis and Lyme disease.

Bevorzugt handelt es sich bei dem polyneuropathischen Schmerz um Schmerz, welcher als Ursache eine Polyneuropathie im Sinne der ICD-10 hat (Internationale statistische Klassifikation der Krankheiten und verwandter Gesundheitsprobleme, WHO Ausgabe, vorzugsweise Stand 2008). Bevorzugt ist die Polyneuropathie ausgewählt aus paraneoplastischer Polyneuropathie, hereditärer und idiopathischer Neuropathie [G60], Polyneuritis [G61], sonstigen Polyneuropathien [G62], Polyneuropathie bei anderenorts klassifizierten Krankheiten [G63], Neuralgie o.n.A. [M79.2-], Neuritis o.n.A. [M79.2-], Peripherer Neuritis während der Schwangerschaft [026.83] und Radikulitis o.n.A. [M54.1-].The polyneuropathic pain is preferably pain which has as its cause a polyneuropathy within the meaning of ICD-10 (International Statistical Classification of Diseases and Related Health Problems, WHO edition, preferably as of 2008). Polyneuropathy is preferably selected from paraneoplastic polyneuropathy, hereditary and idiopathic neuropathy [G60], polyneuritis [G61], other polyneuropathies [G62], polyneuropathy in diseases classified elsewhere [G63], neuralgia or the like. [M79.2-], Neuritis o.n.A. [M79.2-], peripheral neuritis during pregnancy [026.83] and radiculitis o.n.A. [M54.1-].

Handelt es sich um eine hereditäre oder idiopathische Neuropathie [G60], so ist diese vorzugsweise ausgewählt aus der Gruppe bestehend aus hereditärer sensomotorischer Neuropathie [G60.0] (Charcot-Marie-Tooth-Hoffmann-Syndrom, Dejerine-Sottas-Krankheit, hereditäre sensomotorische Neuropathie, Typ I-IV, hypertrophische Neuropathie des Kleinkindalters, Peronäale Muskelatrophie (axonaler Typ) (hypertrophische Form), Roussy-Lévy-Syndrom); Refsum-Krankheit [G60.1]; Neuropathie in Verbindung mit hereditärer Ataxie [G60.2]; idiopathischer progressiver Neuropathie [G60.3]; sonstiger hereditärer und idiopathischer Neuropathie [G60.8] (Morvan-Krankheit, Nélaton-Syndrom, Sensible Neuropathie: dominant vererbt oder rezessiv vererbt); und hereditärer und idiopathischer Neuropathie, nicht näher bezeichnet [G60.9].If it is a hereditary or idiopathic neuropathy [G60], it is preferably selected from the group consisting of hereditary sensorimotor neuropathy [G60.0] (Charcot-Marie-Tooth-Hoffmann syndrome, Dejerine-Sottas disease, hereditary sensorimotor Neuropathy, type I-IV, hypertrophic neuropathy of infancy, peroneal muscle atrophy (axonal type) (hypertrophic form), Roussy-Lévy syndrome); Refsum disease [G60.1]; Neuropathy associated with hereditary ataxia [G60.2]; idiopathic progressive neuropathy [G60.3]; other hereditary and idiopathic neuropathy [G60.8] (Morvan disease, Nélaton syndrome, sensory neuropathy: dominant inheritance or recessive inheritance); and hereditary and idiopathic neuropathy, unspecified [G60.9].

Handelt es sich um eine Polyneuritis [G61], so ist diese vorzugsweise ausgewählt aus der Gruppe bestehend aus Guillain-Barré-Syndrom (Polyradikuloneuropathie) [G61.0] (akute (post-) infektiöse Polyneuritis); Serumpolyneuropathie [G61.1], sonstiger Polyneuritiden [G61.8] und Polyneuritis, nicht näher bezeichnet [G91.9].If it is a polyneuritis [G61], it is preferably selected from the group consisting of Guillain-Barré syndrome (polyradiculoneuropathy) [G61.0] (acute (post-) infectious polyneuritis); Serum polyneuropathy [G61.1], other polyneuritides [G61.8] and polyneuritis, unspecified [G91.9].

Handelt es sich um eine sonstige Polyneuropathie [G62], so ist diese vorzugsweise ausgewählt aus der Gruppe bestehend aus arzneimittelinduzierter Polyneuropathie [G62.0], Alkohol-Polyneuropathie [G62.1], Polyneuropathie durch sonstige toxische Agenzien [G62.2], sonstiger näher bezeichneter Polyneuropathie [G62.8] (strahleninduzierte Polyneuropathie, Critical-illness-Polyneuropathie [G62.80], sonstige näher bezeichnete Polyneuropathie [G62.88]) und Polyneuropathie, nicht näher bezeichnet [G62.9] (Neuropathie o.n.A.).In the case of other polyneuropathy [G62], it is preferably selected from the group consisting of drug-induced polyneuropathy [G62.0], alcoholic polyneuropathy [G62.1], polyneuropathy by other toxic agents [G62.2], others Specified polyneuropathy [G62.8] (radiation-induced polyneuropathy, critical illness polyneuropathy [G62.80], other specified polyneuropathy [G62.88]) and polyneuropathy, unspecified [G62.9] (neuropathy NOS).

Handelt es sich um eine Polyneuropathie bei anderenorts klassifizierten Krankheiten [G63], so ist diese vorzugsweise ausgewählt aus der Gruppe bestehend aus Polyneuropathie bei anderenorts klassifizierten infektiösen und parasitären Krankheiten [G63.0] (Polyneuropathie bei: Diphtherie [A36.8†], infektiöser Mononukleose [B27̃.†], Lepra [A30̃.†], Lyme-Krankheit [A69.2†], Mumps [B26.8†], nach Zoster [B02.2†], Spätsyphilis [A52.1†], Spätsyphilis, konnatal [A50.4†], Tuberkulose [A17.8t]); Polyneuropathie bei Neubildungen [G63.1] [COÖ-D48†]; diabetischer Polyneuropathie [G63.2] [E10̃-E14†, vierte Stelle .4]; Polyneuropathie bei sonstigen endokrinen und Stoffwechselkrankheiten [G63.3] [E00̃-E07†, E15̃-E16†, E20--E34†, E70̃-E89†]; Polyneuropathie bei alimentären Mangelzuständen [G63.4] [E40̃-E64†]; Polyneuropathie bei Systemkrankheiten des Bindegewebes [G63.5] [M30̃-M35†]; Polyneuropathie bei sonstigen Krankheiten des Muskel-Skelett-Systems [G63.6] [M00̃-M25†, M40̃-M96†]; und Polyneuropathie bei sonstigen anderenorts klassifizierten Krankheiten [G63.8] (urämische Neuropathie [N18.8†]).If it is a polyneuropathy in diseases classified elsewhere [G63], it is preferably selected from the group consisting of polyneuropathy in infectious and parasitic diseases classified elsewhere [G63.0] (polyneuropathy in: diphtheria [A36.8 †], infectious Mononucleosis [B27. †], leprosy [A30. †], Lyme disease [A69.2 †], mumps [B26.8 †], zoster [B02.2 †], late syphilis [A52.1 †], late syphilis . congenital [A50.4 †], tuberculosis [A17.8t]); Polyneuropathy in neoplasms [G63.1] [COÖ-D48 †]; diabetic polyneuropathy [G63.2] [E10-E14 †, fourth digit .4]; Polyneuropathy in other endocrine and metabolic diseases [G63.3] [E00-E07 †, E15-E16 †, E20- - E34 †, E70-E89 †]; Polyneuropathy in Alimentary Deficiency States [G63.4] [E40-E64 †]; Polyneuropathy in systemic connective tissue disorders [G63.5] [M30-M35 †]; Polyneuropathy in other diseases of the musculoskeletal system [G63.6] [M00-M25 †, M40-M96 †]; and polyneuropathy in other diseases classified elsewhere [G63.8] (uremic neuropathy [N18.8 †]).

In einer besonders bevorzugten Ausführungsform ist der polyneuropathische Schmerz mit diabetischer Polyneuropathie [G63.2] assoziiert. Mehr als die Hälfte aller Diabetiker entwickelt eine Nervenschädigung (Polyneuropathie), wenn sie länger als zehn Jahre an Diabetes erkrankt sind. Nimmt man alle Typ-1 und Typ-2 Diabetiker zusammen, leiden etwa 30 Prozent darunter.In a particularly preferred embodiment, the polyneuropathic pain is associated with diabetic polyneuropathy [G63.2]. More than half of all diabetics develop nerve damage (polyneuropathy) if they have been suffering from diabetes for more than ten years. If you take all type 1 and type 2 diabetics together, about 30 percent suffer from it.

In einer anderen, besonders bevorzugten Ausführungsform ist der polyneuropathische Schmerz durch toxische Agenzien induziert (chemisch induzierte Polyneuropathie), vorzugsweise durch Arzneimittel (z.B. Chemotherapeutika) [G62.0] oder Alkohol [G62.1]. Es sind verschiedene toxische Agenzien bekannt, welche eine Polyneuropathie induzieren können. Beispiele für Arzneimittel sind Cisplatin, Didanosin, Stavudin und Zalcitabin.In another particularly preferred embodiment, the polyneuropathic pain is induced by toxic agents (chemically induced polyneuropathy), preferably by drugs (e.g., chemotherapeutics) [G62.0] or alcohol [G62.1]. Various toxic agents are known which can induce polyneuropathy. Examples of drugs are cisplatin, didanosine, stavudine and zalcitabine.

Die nachfolgenden Beispiele illustrieren die Erfindung, sind jedoch nicht einschränkend auszulegen.The following examples illustrate the invention, but are not intended to be limiting.

BeispieleExamples

Männliche Sprague Dawley Ratten (140-180 g, Janvier, Frankreich) wurden bei Standardbedingungen (6.00-18.00 Uhr Licht, 18.00 Uhr-6.00 Uhr Dunkelheit; 20-24°C Raumtemperatur, 35-70% relative Luftfeuchte; Leitungswasser und Standardfutter (ad libitum) in Gruppen zu fünf Tieren in Macrolon Typ 4 Käfigen gehalten.Male Sprague Dawley rats (140-180 g, Janvier, France) were placed under standard conditions (6:00 am-6: 00 pm light, 6:00 pm-6: 00 pm, 20-24 ° C room temperature, 35-70% relative humidity, tap water and standard diet (ad libitum) in groups of five animals in Macrolon type 4 cages.

Vergleichsbeispiel - mononeuropathischer SchmerzComparative Example - Mononeuropathic Pain

Die Untersuchung erfolgte gemäß Bennett et al., Pain, 1988, 33, 87-107 .The investigation was carried out according to Bennett et al., Pain, 1988, 33, 87-107 ,

Unter Pentobarbitainarkose (Narcocen, 60 mg/kg i.p., Merial GmbH, Deutschland) wurden unilateral vier lose Ligaturen des rechten nervus ischiaticus gesetzt. Die Tiere entwickelten an der vom geschädigten Nerv innervierten Pfote eine Überempfindlichkeit, die nach einer Erholungsphase von einer Woche über etwa vier Wochen mit Hilfe einer 4°C kalten Metallplatte quantifiziert wurde (Kälte-Allodynie). Die Tiere wurden für einen Zeitraum von 2 min. auf dieser Platte beobachtet und die Anzahl der Wegziehreaktionen der geschädigten Pfote wurde gemessen. Bezogen auf den Vorwert vor Substanzapplikation wurde die Substanzwirkung über einen Zeitraum von einer Stunde an vier Zeitpunkten (15, 30, 45, 60 min nach Applikation) bestimmt. Die Hemmung der Kälte-Allodynie zu den einzelnen Messzeitpunkten wurde in Prozent Wirkung zum individuellen Vortest (%MPE) ausgedrückt, wobei der Vortest 0% MPE und eine vollständige Hemmung (0 Wegziehreaktionen pro 2 min) 100% MPE entsprach. Die Gruppengröße betrug n=10. Die Signifikanz einer Substanzwirkung wurde auf Basis der prozentualen Hemmwerte gegen die Vehikelgruppe mittels zweifaktorieller Varianzanalyse und posthoc Analyse nach Bonferroni, der ED50-Wert über lineare Regressionsanalyse für die einzelnen Messpunkte oder die Fläche unter der Kurve (AUC) bestimmt.Under pentobarbitine anesthesia (Narcocen, 60 mg / kg ip, Merial GmbH, Germany), four loose ligatures of the right nervus ischiaticus were placed unilaterally. The animals developed hypersensitivity to the paw innervated by the damaged nerve, which was quantified after a recovery period of one week for about four weeks using a 4 ° C cold metal plate (cold allodynia). The animals were kept for a period of 2 min. observed on this plate and the number of pull-away responses of the injured paw was measured. Based on the initial value before substance administration, the substance effect was determined over a period of one hour at four time points (15, 30, 45, 60 min after application). Inhibition of cold allodynia at each time point of measurement was expressed as the percent pretreatment (% MPE) effect, with the pretest corresponding to 0% MPE and complete inhibition (0 eviction responses per 2 min) to 100% MPE. The group size was n = 10. The significance of a substance effect was determined on the basis of the percent inhibition values against the vehicle group by means of two-factorial analysis of variance and post hoc analysis according to Bonferroni, the ED 50 value via linear regression analysis for the individual measurement points or the area under the curve (AUC).

(1 R,2R)- 3-(2-Dimethylaminomethyl-cyclohexyl)-phenol (10-31,6 mg/kg i.p.) führte zu einer dosisabhängigen Hemmung der Kälte-Allodynie. Die minimal wirksame Dosis, bei der eine statistisch signifikante Hemmung erfolgte, lag bei 21,5 mg/kg i.p. Der maximale Effekt betrug 80% MPE 15 min nach Gabe von 31,6 mg/kg, der ED50-Wert (95% VB) betrug 17,6 (14,1-21,4) mg/kg 30 min nach Applikation.(1R, 2R) - 3- (2-Dimethylaminomethyl-cyclohexyl) -phenol (10-31.6 mg / kg ip) resulted in a dose-dependent inhibition of cold allodynia. The minimal effective dose at which a statistically significant inhibition occurred was 21.5 mg / kg ip. The maximum effect was 80% MPE 15 min after administration of 31.6 mg / kg, the ED 50 value (95% VB ) was 17.6 (14.1-21.4) mg / kg 30 min after application.

Die gemessenen Ergebnisse sind in nachfolgender Tabelle zusammengefasst (Hemmung der Kälte-Allodynie in % MPE; * < 0.05 gegen Vehikel; n.s. nicht signifikant gegen Vehikel): Dosis (%MPE) 15 min 30 min 45 min 60 min 10 MW 22,16 20,93 8,60 9,23 SEM 9,14 10,08 7,05 7,74 Signifikanz n.s. n.s. n.s. n.s. 21,5 MW 56,62 61,06 34,96 16,33 SEM 8,65 7,25 10,01 11,37 Signifikanz * * n.s. n.s. 31,6 MW 80,03 79,15 61,68 21,18 SEM 10,96 7,25 10,16 9,10 Signifikanz * * * n.s. The measured results are summarized in the following table (inhibition of cold allodynia in% MPE, * <0.05 versus vehicle, ns not significant against vehicle): dose (% MPE) 15 minutes 30 min 45 min 60 min 10 MW 22.16 20.93 8.60 9.23 SEM 9.14 10.08 7.05 7.74 significance ns ns ns ns 21.5 MW 56.62 61.06 34.96 16.33 SEM 8.65 7.25 10.01 11.37 significance * * ns ns 31.6 MW 80.03 79.15 61.68 21.18 SEM 10.96 7.25 10.16 9.10 significance * * * ns

Beispiel - polvneuropathischer SchmerzExample - polvneuropathic pain

Die Untersuchung erfolgte gemäß Authier et al., Neuroreport, 1999, 10, 965-8.The study was performed according to Authier et al., Neuroreport, 1999, 10, 965-8.

Ratten wurden an fünf Tagen (Tag 4, 6, 8, 10, 12) mit Vehikel (0,9% NaCl) oder Vincristin (200 µg/kg i.v.) behandelt (1 ml/kg), was zu einer kumulativen Vincristin-Dosis von 1 mg/kg führte. Drei Tage nach der letzten Vincristin Behandlung hatten die Tiere eine Überempfindlichkeit gegen Kälte (Kälte-Allodynie) entwickelt, die über einen Zeitraum von drei Wochen anhielt. Zum Test wurden die Tiere unter einer Plastikhaube auf einen Gitterrost gesetzt und nach Habituation wurde die Kälte-Allodynie quantifiziert. Dazu wurde ein Tropfen Aceton (10 µl) mittels einer Spritze und einen dünnen Plastikschlauch vorsichtig auf eine Hinterpfote aufgebracht. Die Anzahl der induzierten Wegziehreaktionen (Schütteln, Stampfen oder Lecken) wurde über einen Zeitraum von 30 sec aufgenommen. Die kumulative Anzahl von 5 Stimulierungen (im Abstand von je 5 min) wurde vor und zu verschiedenen Zeiten nach der Substanz- oder Vehikelgabe bestimmt. Im Vergleich zum jeweiligen Vortest (0% MPE) und zur wöchentlichen Vehikelkontrollgruppe wurde der prozentuale Hemmwert (% MPE) bestimmt (100% MPE = 0 Wegziehreaktionen). Die Gruppengröße betrug üblicherweise n=10. Die Signifikanz einer Substanzwirkung wurde auf Basis der prozentualen Hemmwerte gegen die Vehikelgruppe mittels zweifaktorieller Varianzanalyse und posthoc Analyse nach Bonferroni, der ED50-Wert über lineare Regressionsanalyse für die einzelnen Messpunkte bestimmt.Rats were treated with vehicle (0.9% NaCl) or vincristine (200 μg / kg iv) (1 ml / kg) on five days (day 4, 6, 8, 10, 12) resulting in a cumulative vincristine dose of 1 mg / kg. Three days after the last vincristine treatment, the animals had a hypersensitivity developed against cold (cold allodynia), which lasted over a period of three weeks. For testing, the animals were placed under a plastic hood on a grid and after Habituation the cold allodynia was quantified. To do this, one drop of acetone (10 μl) was carefully applied to a hind paw using a syringe and a thin plastic tube. The number of induced pull-out reactions (shaking, pounding or leaking) was recorded over a period of 30 seconds. The cumulative number of 5 stimulations (5 min apart) was determined before and at various times after drug or vehicle delivery. Compared to the respective pretest (0% MPE) and to the weekly vehicle control group, the percentage inhibition value (% MPE) was determined (100% MPE = 0 withdrawal reactions). The group size was usually n = 10. The significance of a substance effect was determined on the basis of the percentage inhibition values against the vehicle group by means of two-factorial analysis of variance and post hoc analysis according to Bonferroni, the ED 50 value via linear regression analysis for the individual measurement points.

(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol (Fexeladol) (10-21,5 mg/kg i.p.) führte zu einer dosisabhängigen Hemmung der Kälte-Allodynie. Die minimal wirksame Dosis, bei der eine statistisch signifikante Hemmung erfolgte, lag bei 4,64 mg/kg i.p. Der maximale Effekt betrug 74% MPE 30 min nach Gabe von 21,5 mg/kg, der ED50-Wert (95% VB) betrug 5,7 (3,3-11,1). Die gemessenen Ergebnisse sind in nachfolgender Tabelle zusammengefasst (Hemmung der Kälte-Allodynie in % MPE; * < 0.05 gegen Vehikel; n.s. nicht signifikant gegen Vehikel): Dosis (%MPE) 30 min 180 min 10 MW -28,9 -22,2 SEM 23,8 23,0 Signifikanz n.s. n.s. 2,15 MW 48,4 -37,7 SEM 8,0 19,3 Signifikanz n.s. n.s. 4,64 MW 67,9 22,6 SEM 5,3 12,2 Signifikanz * n.s. 10 MW 58,7 20,8 SEM 17,7 13,8 Signifikanz n.s. n.s. 21,5 MW 74,2 15,2 SEM 12,3 10,0 Signifikanz * n.s. (1R, 2R) -3- (2-Dimethylaminomethyl-cyclohexyl) -phenol (Fexeladol) (10-21.5 mg / kg ip) resulted in a dose-dependent inhibition of cold allodynia. The minimum effective dose at which a statistically significant inhibition occurred was 4.64 mg / kg ip. The maximum effect was 74% MPE 30 min after administration of 21.5 mg / kg, the ED 50 value (95% VB ) was 5.7 (3.3-11.1). The measured results are summarized in the following table (inhibition of cold allodynia in% MPE, * <0.05 versus vehicle, ns not significant against vehicle): dose (% MPE) 30 min 180 min 10 MW -28.9 -22.2 SEM 23.8 23.0 significance ns ns 2.15 MW 48.4 -37.7 SEM 8.0 19.3 significance ns ns 4.64 MW 67.9 22.6 SEM 5.3 12.2 significance * ns 10 MW 58.7 20.8 SEM 17.7 13.8 significance ns ns 21.5 MW 74.2 15.2 SEM 12.3 10.0 significance * ns

Die vorstehenden experimentellen Ergebnisse belegen, dass (1 R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol (Faxeladol) bei mono- und polyneuropathischem Schmerz eine dosisabhängige Hemmung der Kälte-Allodynie bewirkt. Ein signifikanter Unterschied ist im Hinblick auf die Wirkstärke in beiden Tiermodellen zu beobachten - während im polyneuropathischen Schmerzmodell bereits eine signifikante Hemmung bei 4,64 mg/kg i.p. beobachtet wird, tritt im mononeuropathischen Schmerzmodell eine signifikante Hemmung erst bei 21,5 mg/kg i.p. auf, d.h. bei einer mehr als viermal höheren Dosierung. Ähnlich verhält sich der ED50-Wert, der zum gleichen Zeitpunkt nach Verabreichung (30 min) im polyneuropatischen Schmerzmodell 5,7 mg/kg i.p. und im mononeuropathischen Schmerzmodell 17,6 mg/kg i.p. beträgt, also im polyneuropathischen Schmerzmodell um etwa einen Faktor 3 wirksamer ist.The above experimental results demonstrate that (1R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol (faxeladol) in mono- and polyneuropathic pain dose-dependent inhibition of cold allodynia causes. A significant difference can be observed with regard to the potency in both animal models - while in the polyneuropathic pain model a significant inhibition is already observed at 4.64 mg / kg ip, in the mononeuropathic pain model a significant inhibition only occurs at 21.5 mg / kg ip on, ie at a more than four times higher dosage. Similarly, the ED 50 value at the same time after administration (30 min) in the polyneuropathic pain model is 5.7 mg / kg ip and in the mononeuropathic pain model is 17.6 mg / kg ip, ie approximately one factor in the polyneuropathic pain model 3 is more effective.

Diese Daten belegen, dass (1 R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol (Faxeladol) bzw. seine pharmazeutisch verträglichen Salze für die Behandlung von polyneuropathischem Schmerz in besonderer Weise geeignet ist.These data show that (1R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol (faxeladol) or its pharmaceutically acceptable salts is particularly suitable for the treatment of polyneuropathic pain.

Claims (10)

Verwendung des Wirkstoffs 3-(2-Dimethylaminomethyl-cyclohexyl)-phenol oder eines seiner pharmazeutisch verträglichen Salze zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von polyneuropathischem Schmerz.Use of the active ingredient 3- (2-dimethylaminomethylcyclohexyl) phenol or one of its pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for the treatment of polyneuropathic pain. Verwendung nach Anspruch 1, dadurch gekennzeichnet, dass der Wirkstoff als (1 R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol vorliegt.Use according to claim 1, characterized in that the active ingredient is present as (1R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol. Verwendung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass der Wirkstoff als Maleat vorliegt.Use according to claim 1 or 2, characterized in that the active ingredient is present as maleate. Verwendung nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass die pharmazeutische Zusammensetzung eine feste oder flüssige Darreichungsform ist.Use according to one of the preceding claims, characterized in that the pharmaceutical composition is a solid or liquid dosage form. Verwendung nach Anspruch 4, dadurch gekennzeichnet, dass die Darreichungsform zur oralen Verabreichung konfektioniert ist.Use according to claim 4, characterized in that the dosage form is formulated for oral administration. Verwendung nach Anspruch 4 oder 5, dadurch gekennzeichnet, dass die Darreichungsform zur ein-, zwei- oder dreimal täglichen Verabreichung konfektioniert ist.Use according to claim 4 or 5, characterized in that the dosage form for one, two or three times daily administration is made up. Verwendung nach einem der Ansprüche 4 bis 6, dadurch gekennzeichnet, dass die Darreichungsform unter in vitro Bedingungen nach 1 h wenigstens 20 Gew.-% des ursprünglich in der Darreichungsform enthaltenen Wirkstoffs freisetzt.Use according to one of claims 4 to 6, characterized in that the dosage form releases under in vitro conditions after 1 h at least 20 wt .-% of the active substance originally contained in the dosage form. Verwendung nach einem der Ansprüche 4 bis 7, dadurch gekennzeichnet, dass die Darreichungsform den Wirkstoff in einer Dosierung im Bereich von 15 bis 700 mg enthält, bezogen auf die freie Base.Use according to one of claims 4 to 7, characterized in that the dosage form contains the active ingredient in a dosage in the range of 15 to 700 mg, based on the free base. Verwendung nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass der Schmerz peripherer polyneuropathischer Schmerz oder zentraler polyneuropathischer Schmerz ist.Use according to any one of the preceding claims, characterized in that the pain is peripheral polyneuropathic pain or central polyneuropathic pain. Verwendung nach Anspruch 9, dadurch gekennzeichnet, dass der polyneuropathische Schmerz mit diabetischer Polyneuropathie oder postherpetischer Neuralgie assoziiert ist.Use according to claim 9, characterized in that the polyneuropathic pain is associated with diabetic polyneuropathy or postherpetic neuralgia.
EP08002013A 2008-02-04 2008-02-04 3-(2-dimethyl amino methyl-cyclohexyl) phenol for treating polyneuropathic pain Withdrawn EP2085081A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP08002013A EP2085081A1 (en) 2008-02-04 2008-02-04 3-(2-dimethyl amino methyl-cyclohexyl) phenol for treating polyneuropathic pain
EP09708857A EP2259783A2 (en) 2008-02-04 2009-02-02 3-(2-dimethylaminomethyl-cyclohexyl)-phenol against polyneuropathic pain
PCT/EP2009/000655 WO2009098008A2 (en) 2008-02-04 2009-02-02 3-(2-dimethylaminomethyl-cyclohexyl)-phenol against polyneuropathic pain
US12/364,108 US20090197960A1 (en) 2008-02-04 2009-02-02 Method of Inhibiting Polyneuropathic Pain with 3-(2-Dimethylaminomethylcyclohexyl) Phenol
CA2712637A CA2712637A1 (en) 2008-02-04 2009-02-02 3-(2-dimethylaminomethyl-cyclohexyl)-phenol against polyneuropathic pain

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP08002013A EP2085081A1 (en) 2008-02-04 2008-02-04 3-(2-dimethyl amino methyl-cyclohexyl) phenol for treating polyneuropathic pain

Publications (1)

Publication Number Publication Date
EP2085081A1 true EP2085081A1 (en) 2009-08-05

Family

ID=39471938

Family Applications (2)

Application Number Title Priority Date Filing Date
EP08002013A Withdrawn EP2085081A1 (en) 2008-02-04 2008-02-04 3-(2-dimethyl amino methyl-cyclohexyl) phenol for treating polyneuropathic pain
EP09708857A Withdrawn EP2259783A2 (en) 2008-02-04 2009-02-02 3-(2-dimethylaminomethyl-cyclohexyl)-phenol against polyneuropathic pain

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP09708857A Withdrawn EP2259783A2 (en) 2008-02-04 2009-02-02 3-(2-dimethylaminomethyl-cyclohexyl)-phenol against polyneuropathic pain

Country Status (4)

Country Link
US (1) US20090197960A1 (en)
EP (2) EP2085081A1 (en)
CA (1) CA2712637A1 (en)
WO (1) WO2009098008A2 (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0735506A2 (en) * 1995-02-09 1996-10-02 Shoei Printing Co. Ltd. Identification card and its manufacture
DE19525137A1 (en) 1995-07-11 1997-01-16 Gruenenthal Gmbh 6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds as active pharmaceutical ingredients
WO2004009067A1 (en) 2002-07-19 2004-01-29 Grünenthal GmbH 1-phenyl-2-dimethylaminomethyl cyclohexane compounds used for the therapy of depressive symptoms, pain, and incontinence
WO2004047823A1 (en) 2002-11-22 2004-06-10 Grünenthal GmbH Combination of selected analgesics and cox-ii inhibitors
WO2005009329A2 (en) 2003-07-24 2005-02-03 Grünenthal GmbH Medicament containing 6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol with delayed release of active ingredients
WO2007031326A2 (en) * 2005-09-15 2007-03-22 Grünenthal GmbH 3-(2-dimethylaminomethyl cyclohexyl) phenol retard formulation
DE102005034974A1 (en) 2005-07-22 2007-04-19 Grünenthal GmbH Salt of dimethylaminomethyl-phenyl-cyclohexane and its crystalline forms

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050182131A1 (en) * 2002-07-19 2005-08-18 Gruenenthal Gmbh 1-Phenyl-2-dimethylaminomethyl cyclohexane compounds and therapies for depressive symptoms, pain and incontinence
EP2336103A3 (en) * 2005-07-22 2011-07-20 Grünenthal GmbH HCL-polymorphs of 3-[2-(Dimethylamino)methyl-(cyclohex-1-yl)]phenol
US7884247B2 (en) * 2005-07-22 2011-02-08 Gruenenthal Gmbh Salt of dimethylaminomethyl-phenyl-cyclohexane and crystalline forms thereof
US20070032551A1 (en) * 2005-07-22 2007-02-08 Gruenenthal Gmbh Salt of dimethylaminomethyl-phenyl-cyclohexane and crystalline forms thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0735506A2 (en) * 1995-02-09 1996-10-02 Shoei Printing Co. Ltd. Identification card and its manufacture
DE19525137A1 (en) 1995-07-11 1997-01-16 Gruenenthal Gmbh 6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds as active pharmaceutical ingredients
US5733936A (en) 1995-07-11 1998-03-31 Gruenenthal Gmbh 6-dimethylaminomethyl-1-phenyl-cyclohexane compounds as pharmaceutical active ingredients
WO2004009067A1 (en) 2002-07-19 2004-01-29 Grünenthal GmbH 1-phenyl-2-dimethylaminomethyl cyclohexane compounds used for the therapy of depressive symptoms, pain, and incontinence
WO2004047823A1 (en) 2002-11-22 2004-06-10 Grünenthal GmbH Combination of selected analgesics and cox-ii inhibitors
WO2005009329A2 (en) 2003-07-24 2005-02-03 Grünenthal GmbH Medicament containing 6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol with delayed release of active ingredients
DE102005034974A1 (en) 2005-07-22 2007-04-19 Grünenthal GmbH Salt of dimethylaminomethyl-phenyl-cyclohexane and its crystalline forms
WO2007031326A2 (en) * 2005-09-15 2007-03-22 Grünenthal GmbH 3-(2-dimethylaminomethyl cyclohexyl) phenol retard formulation

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Pschyrembel Klinisches Wörterbuch", 2004, DE GRUYTER, BERLIN, XP002483498 *
AUTHIER ET AL., NEUROREPORT, vol. 10, 1999, pages 965 - 8
B.S. GALER ET AL., NEUROLOGY, vol. 48, 1997, pages 332 - 8
BENNETT ET AL., PAIN, vol. 33, 1988, pages 87 - 107
H. CHEN ET AL., MAYO CLIN PROC., vol. 79, 2004, pages 1533 - 45
HRSG. A.R. GENNARO: "Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
M. NAMAKA ET AL., CLIN THER., vol. 26, 2004, pages 951 - 79
SINDRUP S H ET AL: "Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action.", PAIN DEC 1999, vol. 83, no. 3, December 1999 (1999-12-01), pages 389 - 400, XP002483497, ISSN: 0304-3959 *

Also Published As

Publication number Publication date
WO2009098008A2 (en) 2009-08-13
CA2712637A1 (en) 2009-08-13
EP2259783A2 (en) 2010-12-15
US20090197960A1 (en) 2009-08-06
WO2009098008A3 (en) 2009-12-10

Similar Documents

Publication Publication Date Title
DE60016602T2 (en) COMPOSITION CONTAINING A TRAMADOL AND AN ANTICONVULSIVE MEDICAMENT
DE69929041T2 (en) USE OF CABERGOLIN FOR THE TREATMENT OF &#34;RESTLESS LEGS SYNDROME&#34;
EP2117525B1 (en) Use of 1-phenyl-3-dimethylamino-propane compounds for the therapy of neuropathy pain
EP2148669B1 (en) Tapentadol for treating pain from arthritis
EP1696905B1 (en) Substituted 2-aminotetralines for the preventive treatment of parkinson&#39;s disease
DE69926804T2 (en) DEVICES FOR TREATMENT AND DIAGNOSIS OF RESTLESS LEG SYNDROME
JP2012526832A (en) Composition comprising transnorsertraline and serotonin receptor 1A agonist / antagonist and use thereof
WO2009083115A1 (en) Pharmaceuticals and the production and use thereof in the treatment of painful neuropathies
KR20170120708A (en) Durable treatment with 4-aminopyridine in patients with demyelination
EP2155179B1 (en) Axomadol for treating pain from arthritis
DE69529819T2 (en) NEW COMBINATION OF A BETABLOCKER WITH A LOCAL ANESTHETIC
EP1513533A2 (en) Pharmaceutical active substance combination and the use thereof
CN102026633A (en) 1-amino-alkylcyclohexane derivatives for the treatment of sleep disorders
EP2085081A1 (en) 3-(2-dimethyl amino methyl-cyclohexyl) phenol for treating polyneuropathic pain
WO2012120082A1 (en) Adenosine and derivatives thereof for use in pain therapy
DE10163421A1 (en) Use of (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol as an anti-emetic
WO1998058639A1 (en) Synergistically acting compositions for selectively combating tumor tissue
DE69631597T2 (en) COMBINATION OF A BETA RECEPTOR BLOCKER AND AN OPIOID
EP1368023A1 (en) Utilization of buprenorphine in urinary incontinence therapy
DE19629802A1 (en) Medicines used to treat neuropathies
WO2004064843A2 (en) Compound preparation for dizziness
EP0870499A1 (en) Oral use of (+)-0-Demethyltramadol as analgesic
CH710163A2 (en) Bupropion used to treat multiple sclerosis.
WO2005067916A1 (en) Weak to average strength opioids or combinations of said opioids containing antidepressants for the treatment of depressions and anxiety disorders
DE102004011392A1 (en) Weak to moderate opioids or combinations of these opioids with antidepressants for the treatment of depression, anxiety disorders and pain

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

AKX Designation fees paid
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20100206

REG Reference to a national code

Ref country code: DE

Ref legal event code: 8566